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In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma

Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug devel...

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Autores principales: Halatsch, Marc-Eric, Dwucet, Annika, Schmidt, Carl Julius, Mühlnickel, Julius, Heiland, Tim, Zeiler, Katharina, Siegelin, Markus D., Kast, Richard Eric, Karpel-Massler, Georg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708851/
https://www.ncbi.nlm.nih.gov/pubmed/34959641
http://dx.doi.org/10.3390/ph14121241
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author Halatsch, Marc-Eric
Dwucet, Annika
Schmidt, Carl Julius
Mühlnickel, Julius
Heiland, Tim
Zeiler, Katharina
Siegelin, Markus D.
Kast, Richard Eric
Karpel-Massler, Georg
author_facet Halatsch, Marc-Eric
Dwucet, Annika
Schmidt, Carl Julius
Mühlnickel, Julius
Heiland, Tim
Zeiler, Katharina
Siegelin, Markus D.
Kast, Richard Eric
Karpel-Massler, Georg
author_sort Halatsch, Marc-Eric
collection PubMed
description Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).
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spelling pubmed-87088512021-12-25 In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma Halatsch, Marc-Eric Dwucet, Annika Schmidt, Carl Julius Mühlnickel, Julius Heiland, Tim Zeiler, Katharina Siegelin, Markus D. Kast, Richard Eric Karpel-Massler, Georg Pharmaceuticals (Basel) Article Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378). MDPI 2021-11-29 /pmc/articles/PMC8708851/ /pubmed/34959641 http://dx.doi.org/10.3390/ph14121241 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Halatsch, Marc-Eric
Dwucet, Annika
Schmidt, Carl Julius
Mühlnickel, Julius
Heiland, Tim
Zeiler, Katharina
Siegelin, Markus D.
Kast, Richard Eric
Karpel-Massler, Georg
In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
title In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
title_full In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
title_fullStr In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
title_full_unstemmed In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
title_short In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
title_sort in vitro and clinical compassionate use experiences with the drug-repurposing approach cusp9v3 in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708851/
https://www.ncbi.nlm.nih.gov/pubmed/34959641
http://dx.doi.org/10.3390/ph14121241
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